Thiaxanteones



United States Patent BASIC OF ACRIDONES AND THIAXANTHONES Norbert Steiger, Nutley, N. J., assignor to Hofimann- La Roche Inc}, Nutley, N. J., acorporation of New Jersey No Drawing. Application February 8, 1955,Serial No. 486,983

9 Claims. ((31. 260-219) This invention relates to certain tricyclicheterocycles having a single heterocyclic nitrogen or sulfur atom. Moreparticularly, the invention relates to basically substituted acridonesand thiaxanthones.

The compounds of this invention can be characterized as comprising,respectively,the 9(l0H)-acridone nucleus of Formula I below and thel0-thiaxanthone nucleus. of Formula II below wherein each of said nucleiis substituted by at least one basic ether radical and at least onehalogen as later defined herein.

(III) wherein Z is a bivalent radical selected from the group consistingof imino and thio, and each R is a monovalent radical selected from thegroup consisting of hydrogen, halogen, lower alkyl and di(loweralkyl)-'amino-(lower alkoxy); at least one, but'npt more than'two', ofthe radicals R being a di(lower 'alkyl) -amino-(lower alkoxy) radicaland at least one, but not more than two additional, of the radicals Rbeing a halogen atom and' salts of said bases.

In the compounds of the invention represented by Formula III above, atleast one, but not more than two, of the radicals R attached to thenuclear carbon atoms of the aromatic rings is a di(loweralkyl)-amino-(lower alkoxy) radical, ,e. g. dimethylaminomcthoxy,dimethylaminoethoxy, ,diethylaminoethoxy, dimethylaminopropoxy,diethylaminopropoxy, and the like. At least one, but not more than two,of the additional radicals R at-' 2,732,374 Patented Jan. 24, 1956 2tached to the nuclear carbon atoms of the aromatic rings is a halogen,e. g. chlorine or bromine. radicals R are either hydrogen or lower alkylradicals, e. g. methyl, ethyl, propyl, amyl, and the like, and theseradicals Rneed not be identical.

Compounds of the invention represented by the Formula 111 above arebases and readily form acid addition salts with inorganic andorganicacids, e. g. hydrochloric, hydrobromic, hydriodic, sulfuric,phosphoric, acetic, tartaric, oxalic, citric, ethanesulfonic acids, andthe like. They also form quaternary ammonium salts with acyclic andcyclic quaternizing agents, such as lower alkyl halides (e.- g. methylbromide, ethyl iodide, n-butyl-chloride), di(lower alkyl)-sulfates (e.g. dimethyl sulfate), aralkyl halides (e. g. benzyl bromide), and thelike. Since the bases of Formula III may be monoacidic or polyacidicbases, the salts formed by these bases include the monoand poly-acidaddition salts and monoand poly-quaternary salts. The invention includesnot only the bases of Formula III above, but also the-acid additionsalts and quaternary salts of thosebases; A particularly preferred classof salts is those-formed'by the bases with the nontoxic acids andquaternizing agents conventionally em: ployed in the preparation ofchemotherapeutic substances.

The bases of Formula HI above and their salts are useful aschemotherapeutic agents, e. g. as anthelmintic agents (for instance, incombatting pinworms such as Syplzacia ob'vela'ta); as'antifungal agents(for instance in combatting Trichophyton mentagrophytes and Microsporonlariosum); and as antiprotozoan agents (for instance, in combattingTrypanosoma equiperdum and Trichomon'as vaginalis). The compounds ofthis invention are administered 'in therapeutic dosages in conventionalvehicles.

' A general method for preparing the compounds of Formula III abovecomprises reacting a compound of the formula wherein Z has the samemeaning indicated above; and R is a monovalen t radic'al selected fromthe group consisting of hydrogen, halogen, lower alkyl, and hydroxyl; atleast one, but not more than two, of the radicals R being a hydroxylradical and at least. one, but not more than two additional of theradicals R being a halogen with a di(lower alkyl)-amino-(loweralkyl)-halide in the presence of an acid acceptor, e. g. by heating thereactant of Formula IV together with a halide reactant in an inertorganic solvent in the presence of an alkali metal alkoxide such assodium methoxide. From the bases of Formula IlI, the acid addition saltsand quaternary salts of the invention can be prepared, 'for example, byreacting the base with the appropriate acid or quaternizing agent,preferably in an organic solvent, for example, acetone, ether, etc.

The halogenated starting materials, having the Formula IV above whereinZ represents the imino group, are produccd, for example, by reactingo-chloro benzoic acid or a halogen containing o-chloro benzoic acid witha primary aryl amine containing an ether group such as o-amino anisoleor an amino anisole containing a halogen on the benzene nucleus. Theether group or groups on the acridone formed in this manner areconverted to hydroxy groups by hydrolysis in the presence of aluminumchloride,

for example. The halogenated thiaxanthones correspond- The remaining 7Example I 52 grams of l-methyl-4-hydroxy-6-chloro-9(10H)- acridone, 500cc. of chlorobenzene, 100 cc. of methanol and 16 grams of sodiummethoxide were stirred and heated to 131 until the methanol wasdistilled off. The reaction mixture was then cooled to 100 and 35 gramsof fl-diethylaminoethyl chloride were added. The mixture was refluxedfor 4 hours at 130. The reaction mixture was then cooled below 100 and500 cc. of water and 20 cc. of sodium hydroxide (40%) were added. Themixture was then heated to 90. The reaction mixture was then permittedto stratify. The chlorobenzene layer was separated, then dried oversodium sulfate and concentrated in vacuo.l-rnethyl-4-(B-diethylaminoethoxy)-6-chloro- 9(10H)acridone crystallizedin the form of slightly yellow crystals, M. P. 175176.

Example 2 62 grams of 1-chloro-4-hydroxy-acridone, 500 cc. ofchlorobenzene, 120 cc. of methanol and 18 grams of sodium methoxide werestirred and heated to 130 and the methanol was permitted to distill off.The reaction mixture was then cooled to 100 and 45 grams ofB-diethylaminoethyl chloride were added. The mixture was refluxed at130132 for 4 hours. The temperature was reduced to below 100 and 500 cc.of water and 25 cc. of sodium hydroxide (40%) were added. The reactionmixture was stirred for an additional hour, then permitted to stratify.The chlorobenzene layer was removed and concentrated in vacuo. Theresidue was extracted with 60 cc. of concentrated hydrochloric acid and600 cc. of water on a steam :bath. 5 grams of charcoal were added andthe mixture .was filtered .while hot. The mixture was then cooled toandthe l-chloro-4-(B-diethylaminoethoxy)-9(10H)-acridone' wasprecipitated with 70 cc. of sodium hydroxide (40%). The product wascrystallized from 80% alcohol. The slightly yellow crystals thusobtained melted at 115 Example 3 59 grams of 1-chloro4-hydroxy-thiaxanthone, 16 grams of sodium methoxide, 500 cc. ofchlorobenzene and 100 cc. of methanol were heated to 130 and themethanol was allowed to distill ofi. The mixture was cooled to 100 and45 grams of B-diethylaminoethyl chloride were added. The mixture wasrefluxed for 4 hours at 130-132". The temperature was then reduced tobelow 100 and 20 cc. of sodium hydroxide (40%) and 400 cc. of water wereadded. The mixture was stirred for an additional onehalf hour, thenallowed to stratify. The chlorobenzene layer was separated andconcentrated in vacuo. The free base, l-chloro-4-(fidiethylaminoethoxy)-thiaxanthone, was obtained as a yellow oil.

The free base obtained above was converted to the hyd'rochloride bydissolving it in 400 cc. of acetone. The solution was filtered andchilled to 0. 40 cc. of ethanol- HCl (35%) were added and a light yellowcrystalline precipitate formed. The light yellow, crystallineprecipitate which formed was recrystallized from methanol. Themonohydrochloride thus obtained melted at 227.

36 grams of the freebase obtained according to the first paragraph ofthis example were dissolved in 600 cc. of acetone. To this solution wasadded a' solution of grams of tartaric acid in 25 cc. of ethanol and 100cc. of acetone. The mixture was heated to 55. 1-chloro-4-(B-diethylaminoethoxy) thiaxanthone monotartrate precipitated incrystalline form. Upon recrystallization from 80% alcohol, the tartratemelted at l85-l87.

Example 4 54 grams of 1,6-dichloro-4-hydroxy-acridone, 500 cc. ofchlorobenzene, 15 grams of sodium .methoxideand 100 cc. of methanol wereheated to 132 and the methanol was allowed to distill oil. 45 grams offi-diethylaminoethyl chloride were added as described in Example 3above. The free base was isolated according to the procedure describedin Example 3 and crystallized from ethanol. The light tan, crystalline1,6 dichloro 4 (B-diethylaminoethoxy)-9(10H)-acridone melted at 174-175Example 5 42 grams of thiosalicylic acid and 32 grams of 4-chloro-3-methyl anisole were added to 360 grams of sulfuric acid (96%)while agitating vigorously. The mixture was stirred for four hours at45-50. 50 cc. of fuming sulfuric acid (5% anhydride) were added and themixture was heated for one-half hour at 80. The mixture was drowned inice and water and then filtered. The l-chloro-2-rnethyl-4-meth0xythiaxanthone thus obtained was hydrolyzed by refluxing with 35 grams ofaluminum chloride in 250 cc. of chlorobenzene for 3 hours to obtain1-chloro-2-methyl-4-hydroxy thiaxanthone.

28 grams of 1-chloro-2-methyl-4-hydroxy thiaxanthone, 350 cc. ofchlorobenzene, 60 cc. of methanol and 9 grams of sodium methoxide werestirred and heated. The methanol was permitted to distill off. Thedistillation was completed when the temperature reached 131. The mixturewas cooled to 95, 20 cc. of B-diethylaminoethyl chloride were added andthe mixture was refluxed for 4 Example 6 grams (0.31 mol) of thepotassium salt of o-chloro benzoic acid and 52 grams (0.3 mol) of2-chloro'4- methoxy-S-aminotoluene in 225 cc. of amyl alcohol werecondensed by refluxing for 9 hours in the presence of 4.5 grams ofpotassium carbonate and 2 grams of copper powder.

After cooling to room temperature overnight, 30 cc. of sodium hydroxide(40%) and 600 cc. of water were added. The amyl alcohol was removed bysteam distillation. The aqueous residue was filtered while hot. The

@ filtrate was added with stirring to a mixture of ice and watercontaining 50 cc. of concentrated hydrochloric acid. After stirring forone-half hour, the crude condensation product was filtered off, washedacid free wi h cold tap water and dried under suction. The product,2-(2-' methoxy-4'-chloro-5-methylanilino)benzoic acid, wasrecrystallized from a mixture of 1150 cc. of glacial acetic acid and 500cc. of water, M. P. ZOO-202.

grams (0.22 mol) of the condensation product obtained above was heatedfor 9 hours with 650 grams of polyphosphoric acid on a steam bath. Aftercooling to room temperature, the reaction mixture was carefully dilutedby the dropwise addition of- 800 cc. of water while cooling, andfinallyadded to 2500 cc. of ice and water. After stirring for one hour, thecrude 1-methyl- 2 -chloro-4- methoxy-9(10H)-acridone was filtered off,washed acid free with cold water and dried under suction. The crude 5product was heated with 1000 cc. of water and 15 cc. of sodium hydroxide(40%) at 85 for one-half hour. The solid was filtered ofl", washedalkali free and then dried, first under suction and then in vacuo. Uponcrystallization from chlorobenzene, the compound melted at 193-195.

59 grams (0.216 mol) of 1-methyl-2-chloro-4-methoxy- 9(10H)-acn'donewere refluxed with 95 grams of aluminum chloride in 450 cc. ofchlorobenzene for 5 hours. After cooling to room temperature, thereaction mixture was carefully decomposed with crushed ice. Thechlorobenzene was removed by steam distillation and the crude1-methyl-2-chloro-4-hydroxy-9(10H)-acridone was filtered off. Afterdissolving in a solution of 1000 cc. of water and 100 cc. of sodiumhydroxide (40%) at 85, the product was isolated by precipitation withacetic acid and crystallized from ethanol, M. P. 312314. I

49 grams (0.19 mol) of 1-methyl-2-chloro-4-hydroxy- 9(10H)-acridone werecondensed with 35 grams (0.26 mol) of p-diethylaminoethyl chloride in600 cc. of chlorobenzene in the presence of 13 grams (0.24 mol) ofsodium methoxide by refluxing for 4 hours. 150 cc. of water and 25 cc.of sodium hydroxide (40%) were then added. The reaction mixture wascooled in ice and the crystalline product which separated was filteredoff. The l-rnethyl- 2-chloro-4-(fl-diethylaminoethoxy) -9( lH)-acridonewas recrystallized from ligroin-benzene, M. P. 143-145 The base thusobtained was converted to the hydrochloride by treatment withethanol-HCl in benzene-ether solution. The hydrochloride wascrystallized from ethyl acetate-ethanol-ether, M. P. 241-243.

Example 7 19 grams of 1,7-dichloro-4-hydroxy-thiaxanthone (synthesizedfrom 2-mercapto-4-chloro benzoic acid and p-chloro anisole according tothe method described in Example 5), 360 cc. of chlorobenzene, 60 cc. ofmethanol and 6 grams of sodium methoxide were heated'to 132 and themethanol was allowed to distill off. The mixture was then cooled to 100and 15 cc. of B-diethylaminoethyl chloride were added. The mixture wasrefluxed for 4 hours at 130 to 132. After cooling below 100, 300 cc. ofwater and 10 cc. NaOH (40%) were added. The mixture was stirred forone-half hour then permitted to stratify. The chlorobenzene layer wasseparated and after drying over sodium sulfate, it was concentrated in'vacuo. The oily residue, 1,7-dichloro-4-(fl-diethylaminoethoxy)-thiaxanthone, was dissolved in 300 cc. of acetone and precipitated with10 cc. ethanol-HCI containing 25% HCl.1,7-dichloro-4-(p-diethylaminoethoxy) thiaxanthone hydrochlorideprecipitated as light yellow crystals which were recrystallized from 96%aqueous alcohol, M. P. 222-224".

Example 8 5 grams of 1-methyl-2 chloro-4-(p-diethylaminoethoxy)-9(10H)-acridone were dissolved in 50 cc. of acetone. The mixture wasfiltered and to the filtrate were added in the cold (10 to 1 :5 10 cc.of a 25% solution of methyl bromide in acetone. Upon standing for 24hours, 1-methyl-2-chloro 4 (a diethylaminoethoxy)- 9(l0H)-acridonemethyl bromide crystallized.

I claim:

1. A compound selected from the class consisting of bases having theformula at ll ii a. l l.

wherein Z is a bivalent radical selected from the group consisting ofimino and thio, and each R is a monovalent radical selected from thegroup consisting of hydrogen, halogen, lower alkyl and di-(loweralkyl)-amino-(lower alkoxy); at least one, but not more than two, of theradicals R being a di-(lower alkyl)-amino-(lower alkoxy) radical, and atleast one, but not more than two additional, of the radicals R being ahalogen and salts of said bases.

2. A 9(l0H)-acridone, substituted on the nuclear carbon atoms, whereinone substituent is a di(lower alkyl)- amino-(lower alkoxy) radical and asecond substituent is a halogen.

3. A 9(10I-I)-acridone, substituted on the nuclear carbon atoms, whereinone substituent is a di(lower alkyl)- amino-(lower alkoxy) radical, asecond substituent is a halogen and a third substituent is a lower alkylradical.

4. A thiaxanthone, substituted on the nuclear carbon atoms, wherein onesubstituent is a di(lower alkyl)-ami- Ito-(lower alkoxy) radical and asecond substituent is a halogen.

5. 1 ch1oro-4-(fl-diethylaminoethoxy) 9(10H) acridone. 1

6. lchloro-4-(fl-dietliylaminoethoxy) -thiaxanthone.

7. Acid addition salts ofl-chloro-4-(B-diethylaminoethoxy)-thiaxanthone.

8. 1-chloro 4-(p-diethylaminoethoxy)-thiaxanthone hy drochloride.

9. l-methyl-Z-chloro 4 (3 diethylaminoethoxy)- 9( 10H)acridone.

References Cited in the tile of this patent FOREIGN PATENTS 488,680Germany Jan. 9, 1930

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF BASES HAVING THEFORMULA